Documented cases of fatal and non-fatal torsade de pointes (TdP), a type of lethal ventricular arrhythmia, associated with the use of new chemical entities (NCE) have resulted in the withdrawal of a number of drugs from the market. In further response to these public health concerns, the International Council for Harmonization Guidance (ICH E14) has been implemented to guide drug developers in the conduct of thorough cardiac safety assessments on all NCEs and has since virtually eliminated post-market drug withdrawals due to arrhythmia and sudden cardiac deaths. Beginning from 2005, nearly all new compounds in development have been expected to undergo rigorous testing for their potential to prolong the QT interval (a surrogate marker of proarrhythmia) on an electrocardiogram (ECG).
New drugs seeking regulatory approval typically undergo systematic evaluation of the potential to cause QT prolongation in a Thorough QT (TQT) study in healthy subjects or as part of an intensive assessment of ECGs collected from Phase I trials using exposure response modeling. Prior to characterizing a drug's QT liability in a TQT or Phase I study, subjects with a marked baseline prolongation of QT/QTc interval are generally excluded from participating in a clinical study. For example, subjects with a measured QTc interval in excess of 450 milliseconds during screening for a late-phase study are often excluded from the trial. Underlying QT prolongation has been shown to be associated with a broad range of disease states, including liver disease, oncology, diabetes, rheumatoid arthritis and some central nervous system conditions. The share of subjects who have measured QT prolongation has been shown in studies to be higher than in the population of healthy subjects as a whole. Research studies have also shown that QT prolongation may also be more prevalent in individuals that are older or obese, or that are experiencing depression, anxiety or sleeplessness, which are all conditions or characteristics that may commonly be encountered in clinical trial subjects.
Furthermore, site-based ECG machines and the automated QTc readings they produce are often relied upon to measure the QT/QTc interval for the purpose of making subject inclusion/exclusion decisions, and studies indicate that these automated machine measurements often produce QT measurements that substantively diverge from, and which are often longer than, QT measurements made at centralized ECG core laboratories, resulting in unnecessary patient exclusions and lower patient recruitment yields. Consequently, automated QT/QTc measurements derived from many ECG devices are not accurate or precise enough to optimize correct subject inclusion/exclusion decision making, especially when subjects have an underlying QT/QTc that is close to the exclusion threshold or when ECGs exhibit unusual morphologies. To compensate for these inefficiencies, more subjects are recruited, thus raising costs and the time required to complete a study.
Additionally, even when QT/QTc measurements are made at a centralized ECG core laboratory rather than being derived automatically from ECG devices at a clinical trial site, a significant amount of variability in these measurements may occur based on the quality and variability of the cardiac beats that are selected for measurement. Selecting poor quality cardiac beats, or cardiac beats that contain outlier values compared to most of the other cardiac beats for that subject at that time, may include QT/QTc measurements that do not accurately represent the state of the subject. This can lead to potential issues in any clinical study where QT/QTc is being measured. For example, skewed QT/QTc values generated from mixed quality ECG tracings may unnecessarily exclude otherwise eligible patients and/or incorrectly include ineligible patients that can impact study outcomes. This may result in incorrect conclusions about adverse events or about a drug's overall effect on the QT interval. Finally, drug developers often must report not only QT/QTc measures but also on their drug's effect on PR and QRS intervals, which are other measurements derived from an ECG. Selecting high quality cardiac beats enables more accurate and precise measurements of PR and QRS values. Accordingly, it would be desirable to characterize the quality of an electrocardiogram signal for determining QT liability, as well as for making correct conclusions about a subject's QT, PR, and QRS intervals, and other ECG characteristics.